Adolescence is a time of dramatic development, much of which varies as a function of sex. Also during this time, alcohol use becomes very common. Likely due to heightened plasticity, the adolescent brain is particularly susceptible to the neurotoxic effects of alcohol. While studies have separately documented cross- sectional sex differences in the effects of alcohol on the adolescent brain and hormonal influences on normative adolescent brain development, to fully understand sex-specific adolescent risk and resilience for alcoholism, multimodal prospective longitudinal studies are crucial. To that end, during this funding period, we will assess an additional 120 healthy non-alcohol/drug using 14-16-year-old youth using functional neuroimaging during working memory and decision making, resting state functional neuroimaging, diffusion tensor imaging, neurocognitive assessment, mood/behavior/personality assessment, and serum hormone assays. Together with over 200 youth assessed during the first funding period of the project, all youth will be quarterly monitore for changes in alcohol/drug use, and youth who emerge into heavy alcohol use (as well as a matched non-using control) will be re-assessed at two time points following initiation of heavy drinking behavior. Using a multi-modal longitudinal design, we aim to better understand sex-specific effects of heavy alcohol use on adolescent brain functioning and connectivity, as well as identify premorbid sex-specific neurobiological risk phenotypes that are predictive of problem drinking during adolescence and young adulthood. Further, we will explore moderating variables, such timing and frequency of alcohol and other drug use, as well as the role of gonadal steroids on sex-specific developmental trajectories. Disentangling sex- specific risk for and consequences of alcohol use during adolescence, in relation to normative brain development, and determining which effects may be hormonally influenced, will move the field closer to more personalized prevention and intervention strategies aimed at male and female youth.